AVA-6000

▎药明康德内容团队编辑 本期看点 1. 多肽偶联药物（PDC）AVA6000在治疗唾液腺癌（SGC）患者的1a期临床试验中获得积极数据，疾病控制率（DCR）达90%。 2. 蛋白降解药物BHV-1400在首个人体临床试验中获得积极结果，在最低剂量下只需一次注射，就可在4小时内将致病抗体水平降低60%。 3. PI3Kα共价抑制剂TOS-358在一项1期临床试验中对PI3Kα的靶点作用率达到95%。 药明康德内容团队整理 AVA6000：公布1期临床试验数据 Avacta Therapeutics公司宣布，其在研多肽偶联药物AVA6000在治疗唾液腺癌患者的1a期临床试验中获得积极数据。唾液腺癌是一种在转移性阶段尚无标准治疗方案的疾病。AVA6000是Avacta研发管线中的首个多肽偶联药物，由阿霉素（doxorubicin）与Avacta专有的pre|CISION多肽偶联而成，该多肽可在肿瘤微环境中由成纤维细胞激活蛋白-α（FAP）特异性切割。FAP在大多数实体瘤中，与健康组织相比表达水平显著升高。Avacta的多肽偶联药物利用这一特征在肿瘤微环境中特异性释放活性药物，从而降低系统暴露和毒性，为患者提供最佳治疗效果。 此次公布的数据显示，AVA6000在唾液腺癌患者中实现了显著且具有临床意义的肿瘤缩小。在接受250 mg/m²及以上剂量治疗的10名唾液腺癌患者中，DCR达90%，5名患者肿瘤显著缩小，其中包括一例部分缓解（PR，肿瘤缩小45%）和四例轻微缓解（MR，肿瘤缩小10%-19.5%）。安全性方面，在每两周一次和每三周一次两个剂量组中，AVA6000的耐受性良好，与常规剂量阿霉素相比，其血液学和心脏毒性明显降低。目前尚未在任一剂量组中确定最大耐受剂量（MTD）。 BHV-1400：公布1期临床试验的初步数据 Biohaven公司公布了其蛋白降解药物管线中的双特异性分子BHV-1400的最新结果。BHV-1400是一款基于耶鲁大学（Yale University）的MoDE技术的双特异性分子，它的一端与半乳糖缺乏型IgA1（Gd-IgA1）抗体结合，另一端与肝细胞表面的去唾液酸糖蛋白受体（ASGPR）结合。ASGPR介导肝细胞通过内吞过程，将靶点蛋白吞入细胞内进行降解。IgA肾病是由于Gd-IgA1的过度生产造成的，BHV-1400通过降低血液循环和肾脏中的Gd-IgA1水平，有望从根源治疗IgA肾病。 此次公布的初步数据显示，BHV-1400在首个人体临床试验中获得积极结果，在最低剂量下只需一次注射，就可在4小时内将致病抗体水平降低60%。在某些患者中，观察到在8小时内将Gd-IgA1水平降低70%。此外，Gd-IgA1水平的降低在单次注射后可维持数天。安全性方面，迄今为止，BHV-1400在1期临床试验中的安全性和耐受性良好，未发现具有临床意义的先天和适应性免疫力的变化，并且未观察到剂量限制性毒性。这项研究将继续提高BHV-1400的剂量，探索降低Gd-IgA1水平的范围。基于该研究的积极结果，该公司还计划直接启动关键性临床试验，评估BHV-1400治疗IgA肾病的疗效和安全性。 ▲BHV-1400快速降低Gd-IgA1水平（图片来源：Biohaven公司官网） TOS-358：公布1期临床试验数据 Totus Medicines公司公布了其在研PI3Kα共价抑制剂TOS-358的1期临床试验数据。TOS-358是一款具高度特异性、强效的PI3Kα抑制剂，可在临床前模型中实现近100%的PI3Kα抑制，诱导带有PI3Kα突变的异种移植实体瘤的细胞死亡，包含结直肠癌、肺癌、乳腺癌、卵巢癌、食管癌、头颈癌，且几乎没有观察到非靶向抑制。 此次公布的研究结果表明，TOS-358在低至5 mg每日两次（BID）的剂量下具有泛突变临床活性，对PI3Kα的靶点作用率达到95%，且观察到未经确认的完全缓解（CR）。安全性方面，未报道3/4级毒性。值得注意的是，几名接受给药的患者现在已超过6个月未发生进展。在成功完成1期剂量递增研究后，该公司现在启动了一项扩展研究，针对乳腺癌、子宫内膜癌、尿路上皮癌和头颈癌。 ORIC-944：公布1b期联合治疗试验数据 ORIC Pharmaceuticals公司公布了其选择性PRC2别构抑制剂ORIC-944联用阿帕鲁胺治疗转移性去势抵抗性前列腺癌（mCRPC）的1b期临床试验数据。截至2024年12月10日的数据，6例患者中有3例达到确认的PSA50应答（即PSA水平降低50%），其中2例达到确认的PSA90应答。所有PSA应答均维持≥12周，其中包括一例在38周时仍然持续的、确认的PSA90应答。 Soquelitinib：公布1期临床试验的中期数据 Corvus Pharmaceuticals公司公布了其小分子白细胞介素-2诱导的T细胞激酶（ITK）抑制剂soquelitinib用于治疗中度至重度特应性皮炎的1期临床试验的新中期数据。ITK是一种主要表达于T细胞中的酶，在T细胞和自然杀伤（NK）细胞的免疫功能中起重要作用。通过抑制ITK，soquelitinib有望抑制自身免疫和炎症反应。 此次公布的结果显示，与安慰剂相比，soquelitinib治疗组在研究者总体评估（IGA）评分为0/1（皮肤症状清除或几乎清除）和湿疹面积和严重度指数较基线减少75%（EASI 75）这些临床终点方面显示出良好的疗效特征。在soquelitinib组的19例患者中，26%的患者达到IGA 0/1，37%的患者达到EASI 75。在安慰剂组的7例患者中，没有人达到IGA 0/1，也没有人达到EASI 75。安全性方面，未观察到明显的安全问题，也未发现临床上显著的实验室检测异常。 ▲治疗第28天达到终点IGA 0/1、EASI 75的患者占比（图片来源：参考资料[4]） ISM5411：公布两项1期临床试验数据 英矽智能（Insilico Medicine）公司宣布，其自主研发的候选药物ISM5411已完成在澳大利亚和中国开展的两项1期研究，并取得了积极的初步结果。ISM5411是一种潜在用于治疗炎症性肠病（IBD）的小分子抑制剂，靶向PHD1/2靶点且具有新颖的分子结构，该候选药物设计和优化得到了英矽智能生成化学平台Chemistry42的支持。 此次公布的结果显示，在所有剂量组中ISM5411均表现出良好的安全性和耐受性，并初步验证了肠道限制性药代动力学（PK）特征。基于1期临床试验的积极结果，英矽智能预计将于2025年下半年启动一项评估ISM5411在活动性溃疡性结肠炎患者中的2期临床试验。 MBX 1416：公布1期临床试验数据 MBX Biosciences公司公布了在健康成年受试者中开展的MBX 1416单剂量递增和多剂量递增临床试验的积极结果。MBX 1416是一种长效胰高血糖素样肽1（GLP-1）受体拮抗剂，用于治疗减肥后的低血糖症（PBH）。MBX 1416采用MBX公司新颖、专有的精准内分泌肽（PEP）平台设计，旨在防止PBH患者发生严重低血糖，使他们能够过上更健康、更独立的生活。 此次公布的结果显示，MBX 1416通常安全性和耐受性良好，并且具有良好的药代动力学特征，支持每周一次给药。基于这些结果，该公司计划于2025年下半年在PBH患者中启动一项2期研究，以进一步优化剂量。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料（可上下滑动查看） [1] Avacta Announces Positive New Data from the AVA6000 Phase 1 trial Demonstrating Clinically Meaningful Tumor Shrinkage in Patients with Salivary Gland Cancers. Retrieved January 16, 2025, from https://www.globenewswire.com/news-release/2025/01/16/3010665/0/en/Avacta-Announces-Positive-New-Data-from-the-AVA6000-Phase-1-trial-Demonstrating-Clinically-Meaningful-Tumor-Shrinkage-in-Patients-with-Salivary-Gland-Cancers.html [2] Biohaven Highlights Portfolio Progress, Innovation, and Anticipated Milestones at the 43rd Annual J.P. Morgan Healthcare Conference; Reports Positive Degrader Data with Rapid, Deep, and Selective Lowering of Galactose-Deficient IgA1 with Next Generation Potential Therapy for IgA Nephropathy. Retrieved January 14, 2025, from https://www.prnewswire.com/news-releases/biohaven-highlights-portfolio-progress-innovation-and-anticipated-milestones-at-the-43rd-annual-jp-morgan-healthcare-conference-reports-positive-degrader-data-with-rapid-deep-and-selective-lowering-of-galactose-deficient-ig-302349336.html [3] Totus Medicines Announces Successful Completion of a Phase 1 Dose-Escalation Study and Initiation of an Expansion Trial Evaluating TOS-358, a Covalent PI3Ka Selective Therapy for the Treatment of Select Solid Tumors and Appoints Zelanna Goldberg as Chief Medical Officer. Retrieved January 17, 2025, from https://www.globenewswire.com/news-release/2025/01/10/3007658/0/en/Totus-Medicines-Announces-Successful-Completion-of-a-Phase-1-Dose-Escalation-Study-and-Initiation-of-an-Expansion-Trial-Evaluating-TOS-358-a-Covalent-PI3Ka-Selective-Therapy-for-th.html [4] Corvus Pharmaceuticals Announces Data from Cohort 2 of Placebo-Controlled Phase 1 Clinical Trial of Soquelitinib for Atopic Dermatitis. Retrieved January 17, 2025, from https://www.globenewswire.com/news-release/2025/01/13/3008374/0/en/Corvus-Pharmaceuticals-Announces-Data-from-Cohort-2-of-Placebo-Controlled-Phase-1-Clinical-Trial-of-Soquelitinib-for-Atopic-Dermatitis.html [5] ORIC® Pharmaceuticals Provides Early Phase 1b Combination Data for ORIC-944, Operational Highlights for 2024, and Anticipated Upcoming Milestones. Retrieved January 17, 2025, from https://www.globenewswire.com/news-release/2025/01/13/3008495/0/en/ORIC-Pharmaceuticals-Provides-Early-Phase-1b-Combination-Data-for-ORIC-944-Operational-Highlights-for-2024-and-Anticipated-Upcoming-Milestones.html [6] 英矽智能公布炎症性肠病药物ISM5411两项I期临床试验的积极结果. Retrieved January 17, 2025, from https://www.prnasia.com/story/474986-1.shtml [7] MBX Biosciences Announces Positive Phase 1 Topline Results for MBX 1416 for the Treatment of Post-bariatric Hypoglycemia. Retrieved January 17, 2025, from https://www.globenewswire.com/news-release/2025/01/07/3005223/0/en/MBX-Biosciences-Announces-Positive-Phase-1-Topline-Results-for-MBX-1416-for-the-Treatment-of-Post-bariatric-Hypoglycemia.html [8] Mersana Therapeutics Announces Positive Initial Clinical Data from Phase 1 Clinical Trial of Emiltatug Ledadotin (XMT-1660); Initiation of Expansion in Triple Negative Breast Cancer. Retrieved January 17, 2025, from https://www.globenewswire.com/news-release/2025/01/10/3007493/0/en/Mersana-Therapeutics-Announces-Positive-Initial-Clinical-Data-from-Phase-1-Clinical-Trial-of-Emiltatug-Ledadotin-XMT-1660-Initiation-of-Expansion-in-Triple-Negative-Breast-Cancer.html [9] Axcynsis Therapeutics Receives FDA Clearance for IND Application of AT03-65, a Differentiated CLDN6-Targeting ADC, Powered by AxcynDOT™ Technology. Retrieved January 17, 2025, from https://www.prnewswire.com/news-releases/axcynsis-therapeutics-receives-fda-clearance-for-ind-application-of-at03-65-a-differentiated-cldn6-targeting-adc-powered-by-axcyndot-technology-302350114.html [10] Ocugen, Inc. Announces Positive 2-Year Data Across Multiple Mutations from Phase 1/2 Clinical Trial of OCU400 —A Novel Modifier Gene Therapy for Retinitis Pigmentosa. Retrieved January 17, 2025, from https://www.globenewswire.com/news-release/2025/01/13/3008252/0/en/Ocugen-Inc-Announces-Positive-2-Year-Data-Across-Multiple-Mutations-from-Phase-1-2-Clinical-Trial-of-OCU400-A-Novel-Modifier-Gene-Therapy-for-Retinitis-Pigmentosa.html [11] Verismo Therapeutics Announces First Patient Infused in Phase 1 CELESTIAL-301 Clinical Trial of SynKIR™-310. Retrieved January 17, 2025, from https://www.prnewswire.com/news-releases/verismo-therapeutics-announces-first-patient-infused-in-phase-1-celestial-301-clinical-trial-of-synkir-310-302347464.html [12] Caribou Biosciences Initiates the CB-010 GALLOP Phase 1 Trial in Lupus and Provides Outlook for Multiple Clinical Datasets in 2025. Retrieved January 17, 2025, from https://www.globenewswire.com/news-release/2025/01/13/3008079/0/en/Caribou-Biosciences-Initiates-the-CB-010-GALLOP-Phase-1-Trial-in-Lupus-and-Provides-Outlook-for-Multiple-Clinical-Datasets-in-2025.html [13] Arcturus Therapeutics Announces Initiation of Phase 1 H5N1 Flu Vaccine Trial. Retrieved January 17, 2025, from https://ir.arcturusrx.com/news-releases/news-release-details/arcturus-therapeutics-announces-initiation-phase-1-h5n1-flu [14] Korro Bio Announces Dosing of First Participants in REWRITE Phase 1/2a Study of KRRO-110 for Alpha-1 Antitrypsin Deficiency and Provides Pipeline Update. Retrieved January 17, 2025, from https://www.globenewswire.com/news-release/2025/01/13/3008445/0/en/Korro-Bio-Announces-Dosing-of-First-Participants-in-REWRITE-Phase-1-2a-Study-of-KRRO-110-for-Alpha-1-Antitrypsin-Deficiency-and-Provides-Pipeline-Update.html [15] NextCure Announces First Patient Dosed in the Phase 1 Study of LNCB74 (B7-H4 ADC) as Therapeutic for Treating Multiple Cancers. Retrieved January 17, 2025, from https://ir.nextcure.com/news-releases/news-release-details/nextcure-announces-first-patient-dosed-phase-1-study-lncb74-b7 [16] LAVA Doses First Patient in Phase 1 LAVA-1266 Study in Hematological Cancers. Retrieved January 17, 2025, from https://www.globenewswire.com/news-release/2025/01/10/3007674/0/en/LAVA-Doses-First-Patient-in-Phase-1-LAVA-1266-Study-in-Hematological-Cancers.html [17] Context Therapeutics Announces First Patient Dosed in the Phase 1 Clinical Trial of CTIM-76. Retrieved January 17, 2025, from https://www.globenewswire.com/de/news-release/2025/01/14/3009673/0/en/Context-Therapeutics-Announces-First-Patient-Dosed-in-the-Phase-1-Clinical-Trial-of-CTIM-76.html [18] Ocugen, Inc. Announces First Patient Dosed in Phase 1 Clinical Trial of OCU200—a Novel Integrin-Targeting Biologic for Diabetic Macular Edema. Retrieved January 17, 2025, from https://ir.ocugen.com/news-releases/news-release-details/ocugen-inc-announces-first-patient-dosed-phase-1-clinical-trial [19] ProMIS Neurosciences Initiates Phase 1b Clinical Trial (PRECISE-AD) in Alzheimer’s Disease. Retrieved January 17, 2025, from https://www.promisneurosciences.com/news-media/press-releases/detail/236/promis-neurosciences-initiates-phase-1b-clinical-trial [20] Aptose Announces First AML Patients Dosed with Tuspetinib Triplet Frontline Therapy in TUSCANY Trial. Retrieved January 17, 2025, from https://www.aptose.com/news-media/press-releases/detail/307/aptose-announces-first-aml-patients-dosed-with-tuspetinib [21] ORYZON announces first patient dosed in NCI-sponsored iadademstat in combination with venetoclax and azacitidine clinical trial in first line acute myeloid leukemia. Retrieved January 17, 2025, from https://www.oryzon.com/en/news-events/news/oryzon-announces-first-patient-dosed-nci-sponsored-iadademstat-combination [22] 한미약품-GC녹십자, ‘파브리병’ 국내 1/2상 IND 승인. Retrieved January 17, 2025, from https://www.biospectator.com/news/view/24043 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

Meaningful tumor shrinkage observed in five out of 10 patients with partial and minor responses and 90% disease control rate in patients with salivary gland cancers Phase 1b expansion cohorts screening patients in triple negative breast cancer, soft tissue sarcoma and salivary gland cancer LONDON, UK and PHILADELPHIA, PA, USA I January 16, 2025 I Avacta Therapeutics (AIM: AVCT), a life sciences company developing next generation peptide drug conjugates (PDC) targeting powerful anti-tumor payloads directly to the tumor, today announced compelling new data in patients with salivary gland cancer (SGC) from the ongoing Phase 1a trial of AVA6000 in patients with FAP-positive solid tumors. The data demonstrates robust and meaningful tumor shrinkage in patients with salivary gland cancers, a disease with no standard therapy defined in the metastatic setting. AVA6000 is the first peptide drug conjugate in Avacta’s pipeline and consists of doxorubicin conjugated with Avacta’s proprietary pre|CISION ® peptide, that is specifically cleaved by fibroblast activation protein-alpha (FAP) in the tumor microenvironment. The key findings include: Based on this favorable efficacy and safety data observed in the Phase 1a trial, Avacta has initiated three Phase 1b expansion cohorts in triple negative breast cancer, soft tissue sarcoma and salivary gland cancer in the first and second line setting. Patients are screening and the first patients to be treated in these expansions are expected imminently in the US. Christina Coughlin MD, PhD, CEO of Avacta , commented, “These data highlight the transformative potential of our pre|CISION ® peptide drug conjugates in expanding the efficacy of highly potent therapeutics and support our growing optimism in this program. “Salivary gland cancer is a devastating disease with no established standard of care treatment options. AVA6000 demonstrated a clinically meaningful tumor shrinkage in SGC patients, highlighting its potential as an important new treatment option for patients with SGC and other solid tumors. “We look forward to continuing to work with our investigators and the broader community to explore its potential in SGC and other cancers. We are thrilled to begin enrollment in the expansion cohorts, and this part of the trial will also be conducted in less heavily pretreated patients which will allow us to better understand the potential of AVA6000 in these disease settings with high unmet need.” These results demonstrate preliminary evidence of durable antitumor activity in patients with SGC, supported by ongoing RECIST 1 responses (both partial and minor responses) in a disease setting with no standard of care. SGC accounts for 6-8% of head and neck cancers in the US, with approximately 2,500 cases diagnosed in the US each year 2 . There is no standard of care for SGC once patients have developed distant metastasis, with a five year survival rate of approximately 43%. Clinical data observations: Out of 10 patients with SGC treated at the dose of 250 mg/m 2 and above, 5 patients experienced clinically meaningful disease shrinkage, including a confirmed partial response (PR, 45% tumor shrinkage) and four minor responses (MR, 10-19.5% tumor shrinkage) using RECIST criteria. 1 These data include the following cases: Although these data are reported early in the treatment course of most patients, it is notable that six patients (of the 10 patients with SGC), including all five responders, remain on treatment and a further two patients remain in progression-free follow-up after having received the maximum number of cycles of AVA6000. Only one patient has reported disease progression as best response resulting in the disease control rate of 90% in this group of patients with salivary gland cancers. Treatment with AVA6000 continues to be well-tolerated in both dosing arms, once every two weeks (Q2W) and once every three weeks (Q3W), with reduced hematologic and cardiac toxicities compared to conventional dose doxorubicin at 75 mg/m 2 dosed every 3 weeks. A maximum tolerated dose has not been identified in either arm of the trial. 1 Reduction in the sum of longest diameters (SLD) is used to measure response per RECIST 1.1 with partial responses having at least a 30% reduction and minor responses of between >10% and <30% reduction. 2 American Cancer Society: Key Statistics in Salivary Gland Cancers, www.cancer.org/cancer/types/salivary-gland-cancer.html. About Avacta – avacta.com Avacta Therapeutics is a clinical-stage life sciences company expanding the reach of highly potent cancer therapies with the pre|CISION ® platform. pre|CISION ® is a proprietary warhead delivery systembased on a tumor-specific protease (fibroblast activation protein or FAP) that is designed to concentrate highly potent warheads in the tumor microenvironment while sparing normal tissues. Our innovative pipeline consists of pre|CISION ® peptide drug conjugates (PDC) or Affimer ® drug conjugates (AffDC) that leverage the tumor-specific release mechanism, providing unique benefits over traditional antibody drug conjugates. About the pre|CISION ® Platform The pre|CISION ® platform comprises an anticancer payload conjugated to a proprietary peptide that is a highly specific substrate for fibroblast activation protein (FAP) which is upregulated in most solid tumors compared with healthy tissues. The pre|CISION ® platform harnesses this tumor specific protease to cleave pre|CISION ® peptide drug conjugates and pre|CISION ® antibody/Affimer ® drug conjugates in the tumor microenvironment, thus releasing active payload in the tumor and reducing systemic exposure and toxicity, allowing dosing to be optimized to deliver the best outcomes for patients. About AVA6000: FAP-enabled doxorubicin The lead pre|CISION ® program AVA6000, a peptide drug conjugate form of doxorubicin, is in Phase 1 studies. It has shown an improvement in safety and tolerability in clinical trials to date compared with standard doxorubicin and preliminary signs of clinical activity in multiple patients. SOURCE: Avacta Therapeutics